FREQUENCY-DEPENDENT EFFECTS OF AMITRIPTYLINE AND MAPROTILINE ON CONDUCTION IN THE GUINEA-PIG HIS-PURKINJE-SYSTEM IN-VIVO

In the Cardiac Arrhythmia Suppression Trial antiarrhythmic drug therapy with slow kinetic sodium channel blockers (class Ic antiarrhythmic drugs) was associated with excess mortality, presumably due to drug induced proarrhythmia. It has been suggested that the degree of rate-dependent conduction slowing produced by agents that have sodium channel blocking properties may be related to the proarrhythmic propensity of these agents. In the present study, rate-dependent conduction slowing by the antidepressants amitriptyline and maprotiline was investigated in anesthetized guinea pigs. After electrical ablation of the sinus node the left atrium was stimulated at cycle lengths between 200 ms and 500 ms. His bundle electrograms were registered by means of an epicardial electrode. Drugs were administered by i.v. infusion of 0.2 mg kg(-1) min(-1) for 30 min followed by 0.1 mg kg(-1) min(-1) for up to 30 min. Both drugs produced substantial rate-dependent conduction slowing within the His-Purkinje-system. The relationship between pacing rate and conduction slowing was well fitted by linear regression. The steepness of the regression line was significantly greater for amitriptyline than for maprotiline (slope factors: 9.10 x 10(-4) +/- 7.85 x 10(-5), n = 6, vs. 6.29 x 10(-4) +/- 2.97 x 10(-5), n=6, P<0.001), indicating that conduction slowing by amitriptyline exhibits a greater degree of rate-dependence than conduction slowing by maprotiline. On abruptly changing the driving cycle length from 500 ms to 300 ms, conduction slowing reached a new steady state with-rate constants of 0.83 +/- 0.093 beat(-1) (amitriptyline) and 0.14 +/- 0.05 beat(-1) (maprotiline, P< 0.001). Following interruption of rapid pacing at a cycle length of 250 ms, conduction slowing recovered with time constants of 332.4 +/- 52.8 ms (amitriptyline) and 1088.1 +/- 143.5ms (maprotiline, P= 0.001). Thus, amitriptyline exhibited fast kinetic properties similar to class Ib antiarrhythmic action while the slower kinetic properties of maprotiline resembled those of class Ia agents.